EP2857393B1 - Composé de type amine tertiaire cyclique fusionnée insaturée n-aryle, son procédé de préparation et son application antitumorale - Google Patents

Composé de type amine tertiaire cyclique fusionnée insaturée n-aryle, son procédé de préparation et son application antitumorale Download PDF

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EP2857393B1
EP2857393B1 EP13798070.2A EP13798070A EP2857393B1 EP 2857393 B1 EP2857393 B1 EP 2857393B1 EP 13798070 A EP13798070 A EP 13798070A EP 2857393 B1 EP2857393 B1 EP 2857393B1
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compound
methoxy
arh
alkyl
hydroxyl
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EP2857393A4 (fr
EP2857393A1 (fr
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Lan Xie
Xiaofeng Wang
Kuo-Hsiung Lee
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Institute of Pharmacology and Toxicology of AMMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/40—Nitrogen atoms attached in position 8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

Definitions

  • the present invention relates to an N-aryl unsaturated fused ring tertiary amine compound possessing multiple antitumor activities or a pharmaceutical salt thereof, its preparation method, a pharmaceutical composition containing the compound, and its use in manufacture of an antitumor medicament.
  • Tumors are one of the most serious diseases having strong impact on life of people. Since 1970s, the incidence and mortality rate of cancers in China are on the increase. In urban residents, cancers take the first place of cause of death. According to statistics, 1 of 4 deaths dies of cancer in China.
  • the international pharmaceutical companies develop many novel anti-cancer drugs and therapeutic methods, such as inhibitors targeting cell signal transducers or new vessels, drugs against metastasis or drug-resistance, differentiation inducers, targeting therapy, improving or regulating body immune function, and gene therapy.
  • the existing antitumor and anticancer drugs still cannot meet clinical requirements.
  • WO 95/23141 relates to 4-heterocyclyl-substituted quinazoline derivatives, particularly 4-aminoquinazolines that are useful for the treatment of hyperproliferative diseases, particularly as anticancer agents.
  • WO 96/39145 relates to a method for the selective treatment of cell growth and differentiation characterized by activity of the human epidermal human growth factor type 2 (HER2). More specifically, this invention relates to the use of substituted or unsubstituted mono- or bi-cyclic aryl, heteroaryl, cycloalkyl or heterocycloalkyl compounds in selectively regulating cell growth. Pharmaceutical compositions useful for the selective treatment of cell growth and differentiation are also described.
  • the inventors of the present invention find a series of N-aryl unsaturated fused ring tertiary amine compounds showing significant anticancer activity and broad-spectrum or good selectivity (partial data are shown in Table 1) via inhibition activity tests of synthesized small molecular compounds in many human cancer cell lines (A459, DU145, KB, KB-VIN). The anticancer activities of these compounds are not reported yet. Intensive research on these compounds would lead to develop new antitumor or anticancer drugs with novel structure.
  • the first aspect of the present invention relates to a compound of Formula I or a pharmaceutical salt thereof: wherein,
  • the second aspect of the present invention relates to a method for preparing the compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the third aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the compounds of Formula I or a pharmaceutically acceptable salt thereof or one or more pharmaceutically acceptable carrier or excipient.
  • the fourth aspect of the present invention relates to the compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder such as a tumor, especially a cancer, or alleviating severity of mentioned disease or disorder, wherein the disease is selected from lung cancer, breast cancer, prostate cancer, gastric cancer, nasopharyngeal cancer, colorectal cancer, ovarian cancer, multiple myeloma, melanin, glioblastoma multiforme, lymph cancer, leukemia, kidney cancer, liver tumor, sarcoma and thyroid cancer and other solid tumors.
  • a disease or disorder such as a tumor, especially a cancer, or alleviating severity of mentioned disease or disorder
  • the disease is selected from lung cancer, breast cancer, prostate cancer, gastric cancer, nasopharyngeal cancer, colorectal cancer, ovarian cancer, multiple myeloma, melanin, glioblastoma multiforme, lymph cancer, leukemia, kidney cancer, liver tumor, s
  • alkyl used in the text refers to saturated straight or branched monovalent hydrocarbyl, having 1-12 carbon atoms, preferably having 1-10, 1-8, 1-6, 1-4 or 1-3 carbon atoms.
  • Typical examples of “alkyl” include but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, tert-pentyl, neo-pentyl, hexyl, heptyl, octyl, etc.
  • Typical examples of "alkenyl” include but are not limited to vinyl, propenyl, allyl, butenyl, 2-butenyl, pentenyl, 2-pentenyl, 1,3-pentadienyl, hexenyl, 2-hexenyl, 1,3-hexadienyl, heptenyl, octenyl, etc.
  • Typical examples of “alkynyl” include but are not limited to ethynyl, propynyl, propargyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, etc.
  • amino used in the text refers to -NH 2 .
  • hydroxyl used in the text refers to -OH.
  • cyano used in the text refers to -CN.
  • ester group used in the text refers to group -C(O)OR 10 , wherein R 10 is selected from alkyl and cycloalkyl as defined in the text.
  • Typical examples of "ester group” include but are not limited to -C(O)OCH 3 , -C(O)OC 2 H 5 etc.
  • alkylamino used in the text refers to group -NHR 11 , wherein R 11 is selected from alkyl and cycloalkyl as defined in the text.
  • Typical examples of “alkylamino” include but are not limited to methylamino, ethylamino, propylamino, butylamino, cyclopropylamino, etc.
  • dialkylamino used in the text refers to group -NR 11 R 12 , wherein R 11 and R 12 are independently selected from alkyl and cycloalkyl as defined in the text. Typical examples of “dialkylamino” include but are not limited to dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.
  • acylamino used in the text refers to group -NR 13 C(O)R 14 , wherein R 13 and R 14 are independently selected from hydrogen and the following groups as defined in the text: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
  • Typical examples of "acylamino” include but are not limited to formylamino, acetylamino, cyclohexylcarbonylamino, benzoylamino, benzylcarbonylamino, etc.
  • alkylthio used in the text refers to group -SR 15 , wherein R 15 is alkyl or cycloalkyl as defined in the text.
  • Typical examples of “alkylthio” include but are not limited to methylthio, ethylthio, propylthio, butylthio, cyclohexylthio, etc.
  • cycloalkyl used in the text refers to a saturated cyclic hydrocarbyl having 3-12 carbon atoms and having monocyclic ring or dicyclic ring or multicyclic fused ring (including fused or bridged ring system), preferably having 3-10, 3-8, 5 -8, 3-6 or 5-6 carbon atoms.
  • cycloalkyl include but are not limited to monocyclic ring structure, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl; dicyclic ring structure, such as dicyclo[2.2.1]heptyl, and multicyclic ring structure, such as adamantyl, etc.
  • heterocycloalkyl used in the text refers to a cycloalkyl as defined in the text that contains one, two or more heteroatoms independently selected from N, O and S.
  • Typical examples of “heterocycloalkyl” include but are not limited to tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, piperazinyl, thiazinyl, piperidinyl and morpholinyl, etc.
  • aryl used in the text refers to an unsaturated aromatic carbocyclic ring having 5-14 carbon atoms and one monocyclic ring or two or more fused rings.
  • the aryl preferably has 5-10, 5-8 or 5-6 carbon atoms.
  • Typical examples of "aryl” include but are not limited to phenyl, naphthyl and anthryl.
  • heteroaryl used in the text refers to a 5-14 membered aromatic heterocyclic ring group, comprising monocyclic aromatic heterocyclic ring and multicyclic aromatic ring in which a monocyclic aromatic ring is fused with one or more other aromatic rings. Heteroaryl contains one or two or more heteroatoms selected from O, S or N. The range of the term “heteroaryl” further covers a group, in which an aromatic ring is fused with one or more non-aromatic rings (carbocyclic ring or heterocyclic ring), and the linking group or site is on the aromatic ring or non-aromatic ring.
  • the heteroaryl preferably has 5-10 ring members, more preferably 5-6 ring members.
  • heteroaryl include but are not limited to furyl, imidazolyl, triazolyl, indolyl, tetrazolyl, pyridyl, pteridyl, pyrimidinyl, triazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl.
  • alkoxyl used in the text refers to the group of -OR 16 , wherein R 16 is alkyl or cycloalkyl as defined in the text.
  • Typical examples of "alkoxyl” include but are not limited to methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, cyclohexoxy, cyclopropoxy.
  • acyl used in the text refers to the group of -C(O)R 10 , wherein R 10 is selected from hydrogen and the following groups as defined in the text: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylamino, dialkylamino, aryl or heteroaryl.
  • R 10 is selected from hydrogen and the following groups as defined in the text: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylamino, dialkylamino, aryl or heteroaryl.
  • Typical examples of "acyl” include but are not limited to formyl, acetyl, cyclohexylcarbonyl, benzoyl, etc.
  • halogen used in the text refers to fluorine, chlorine, bromine, or iodine, preferably fluorine, chlorine or bromine.
  • halogenated alkyl used in the text refers to an alkyl mono- or multi-substituted with halogen, such as fluorine, chlorine, bromine or iodine.
  • Preferred halogenated alkyl is chloromethyl, chloroethyl, dichloroethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, etc.
  • cyanoalkyl used in the text refers to an alkyl mono- or multi-substituted with cyano. Preferred cyanoalkyl is cyanomethyl, cyanoethyl, cyanobutyl, etc.
  • hydroxyalkyl used in the text refers to an alkyl mono- or multi-substituted with hydroxyl. Preferred hydroxyalkyl is hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.
  • the groups as defined with the above terms can further be optionally mono- or multi-substituted with -CN, -OH, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 1-4 alkoxyl or halogen.
  • X and Y in Formula I each separately are -CR'R"-.
  • X and Y in Formula I each separately are -CHOR'-.
  • X in Formula I is -NR'-, and Y is -CR'R"-.
  • R 1 in Formula I is alkoxyl or halogen.
  • R 2 in Formula I is alkyl, alkoxyl, halogen, amino, alkylamino or dialkylamino.
  • R 2 in Formula I is alkyl, alkoxyl, halogen, amino or alkylamino.
  • Q and W in Formula I each separately are N.
  • one of Q and W in Formula I independently is N, the other one is CR.
  • Q and W in Formula I each separately are CR.
  • X and Y each independently are -CHOR'-, -C(O)-, -CR'R"- or -NR'-; wherein R' and R" each independently are H, C 1-4 alkyl, C 1-4 alkoxyl or hydroxyl; R 1 represents 1 or 2 substituents optionally existing on benzene ring, independently being alkoxyl, halogen, or hydroxyl; R 2 is alkyl, alkoxyl, halogen, hydroxyl, cyano, amino, alkylamino or dialkylamino; Q and W each independently are N or CR; R is H, halogen, cyano, amino, hydroxyl, C 1-4 alkyl, C 1-4 alkoxyl, hydroxyl C 1-4 alkyl, cyano C 1-4 alkyl, C 1-4 alkylamino or C 1-4 dialkylamino; R 5 and R 6 together with carbon atoms linked to them form
  • the compound of Formula I of the present invention is selected from:
  • the compound of Formula I according to the present invention can be obtained via the following reaction route: wherein R 1 , R 2 , R 5 , R 6 , X, Y, Q, W, n 1 and n 2 are defined as those of the Formula I as above mentioned.
  • an alkali in an amount of 2-10 equivalent or an acid in a catalytic amount of up to 2 equivalent (for example, sodium hydride, cesium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, pyridine, N,N -dimethylaminopridine, or potassium carbonate/potassium carbonate, sodium tert-butoxide, cesium carbonate, potassium carbonate; hydrochloric acid, sulfuric acid, hydrobromic acid or acetic acid), and if necessary, under the action of an auxiliary reagent such as cuprous halide, [bis(diphenylphosphino)ferrocene] dichloropalladium /1,1'-bis(diphenylphosphino)ferrocene, palladium acetate, X-Phos, etc., a substituted halide (Formula III) was reacted with a substituted amine compound (Formula II) in a solvent such as DMF,
  • the reaction can be carried out under condition of microwaves, and the inventory ratio of alkali or acid to the reactants is the same as aforementioned, in a solvent such as DMF, DMSO, tert-butanol, isopropanol, acetone, methanol, ethanol, acetonitrile or 1,4-dioxane, at a temperature of 60-250°C for 5-60 minutes.
  • a solvent such as DMF, DMSO, tert-butanol, isopropanol, acetone, methanol, ethanol, acetonitrile or 1,4-dioxane
  • the compounds of the present invention exhibit strong inhibition activity in tests of many cancer cells. As following described, the compounds show equivalent or better inhibition activity in comparison with positive control drug paclitaxel in inhibition activity tests of lung cancer cells (A549), prostate cancer cells (DU145), nasopharyngeal cancer cells (KB) and drug-resistant nasopharyngeal cancer cells (KB-VIN). It is particularly worth noted that some of the compounds have very strong inhibition activity to drug-resistant KB-VIN cells. Hence, the series of compounds of the present invention have a broad anticancer spectrum, and it is promising to develop many new drugs for treatment of tumor or cancers by intensively studying these compounds.
  • the compounds of the present invention can be used in form of either themselves or their pharmaceutically acceptable salts or solvates.
  • the pharmaceutically acceptable salts of Formula I comprise salts formed with pharmaceutically acceptable inorganic acid or organic acid, or pharmaceutically acceptable inorganic alkali or organic alkali.
  • suitable acid forms salts include salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid, citric acid, pamoic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluene sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, tannic acid.
  • suitable alkali forms salts comprise salts formed with sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N'-dibenzylethanediamine, chloroprocaine, choline, diethanolamine, ethanediamine, N-methylglucosamine and procaine, etc.
  • the compounds of the present invention comprise the compounds of Formula I and their pharmaceutically acceptable salts or solvates.
  • the pharmaceutical composition comprises a compound of Formula I and a conventional pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition can be administered orally or parenterally.
  • the pharmaceutical composition of the present invention can be processed by conventional method to prepare various dosage forms, including but not limited to tablets, capsules, solutions, suspension, granules or injections, for such as oral or parenteral administration.
  • the dose and usage of the compound of the present invention depend on many factors, including age, body weight, gender, natural health condition, nutritional state, activity potency of compound, administration time, metabolic rate, severity of disease, and subjective judgment of doctor.
  • the preferred dose is 0.01 - 100 mg/kg body weight/day.
  • Method I 4-chloro-2-subsituted quinazoline (1.0 mmol), 5-methoxyindoline or 6-substituted-1,2,3,4-tetrahydroquinoline or 7-methoxy-2,3,4,5-tetrahydro-1 H- benzo[b or c]azepine (1.2 mmol) and sodium bicarbonate (3.0 mmol) were added to anhydrous ethanol (5 ml), reacted at room temperature or under refluxing condition for 1-10 h. After the end of reaction, the reactants were poured into ice-water, adjusted pH with 2N hydrochloric acid to 3, extracted with ethyl acetate, dried with anhydrous sodium sulfate. The solvent was removed under vacuum, and the resultant crude product was separated by silica gel column chromatography (eluent: ethyl acetate and petroleum ether for gradient elution, ethyl acetate 5%-80%).
  • This compound was synthesized via 4 steps: 1) 440 mg crude product of 2-methyl-4-(2-nitro-4-methoxy)anilinoquinazoline was prepared according to Method II; 2) the product of step 1) was dissolved in 25 ml of ethyl acetate, 30 mg of Pd/C (10%w/w) was added to perform catalytic hydrogenation reduction at ambient temperature and pressure.
  • step 2 The reaction was complete within 2 h, ethyl acetate was removed under vacuum to obtain 320 mg crude product of 2-methyl-4-(2-amino-4-methoxy)anilinoquinazoline ; 3) the product of step 2) was dissolved in 15 ml of acetone, chloroacetyl chloride 226 mg (2.0 mmol) and anhydrous potassium carbonate (414 mg, 1.5 mmol) were added, the resulting mixture was reacted under ice-bath for 1 h, the reactants was poured into ice-water, extracted with ethyl acetate (3 ⁇ 30 ml), and the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under vacuum to obtain 364 mg rufous solid crude product of 2-methyl-4-(2-(N-1-oxy-2-chloroethyl)amino-4-methoxy) anilinoquinazoline ; 4) the solid of step 3) and anhydrous potassium carbon
  • Methyl 3,5-dibromobenzoate (294 mg, 1.0 mmol), 6-methoxy-1,2,3,4-tetrahydroquinoline (179 mg,1.1 mmol), BINAP (31 mg, 0.05 mmol) and palladium acetate (10 mg, 0.05 mmol) were added to 8 ml of toluene, Cs 2 CO 3 (456 mg, 1.4 mmol) was added under nitrogen gas, heated to 100°C and reacted for 12 h. A small amount of ethyl acetate was added, insoluble substance was removed by filtration, and the crude product was separated with silica gel column chromatography to obtain Compound 26, which was yellow oil, 255 mg, yield 77%.
  • the reactant was poured into about 20 ml of ice-water, adjusted pH with 2N hydrochloric acid to neutral, extracted with AcOEt (3 ⁇ 20 ml), washed with saturatedbrine, dried with anhydrous sodium sulfate, and the crude product was separated by column chromatography to obain Compound 28, which was white solid, 57 mg, yield 90%, melting point: 166-167°C.
  • 6-Chloropurine 150 mg, 0.97 mmol
  • 6-methoxy-1,2,3,4-tetrahydroquinoline 180 mg, 1.10 mmol
  • i -PrOH 15 ml
  • 1 drop of concentrated hydrochloric acid was added, and the resulting mixture was reacted under refluxing for 5 h to obtain 201 mg of target Compound 42, yield 73.6%, white solid.
  • 6-Chloro-2-fluoropurine 110 mg, 0.64 mmol
  • 6-methoxy-1,2,3,4-tetrahydroquinoline 115 mg, 0.70 mmol
  • i -PrOH 15 ml
  • 1 drop of concentrated hydrochloric acid was added, and the resulting mixture was reacted under refluxing for 4 h to obtain 137 mg of target Comopund 43, yield 72.6%, white solid.
  • Example 36 Experiments of inhibiting growth of cancer cells
  • the human cancer cells (A549, DU145, KB, KB-VIN, etc.) were placed in single medium (RPMI-1640 containing 10%(v/v) fetal bovine serum), and the morphological characteristics and growth conditions of cells in medium were observed with microscope.
  • the cells were placed in 2.5 cm culture dish and cultured at 37°C in wet air containing 5% CO 2 . Cell lines grew adhering to wall.
  • the preparation and dilution of samples as well as process for inoculating them to cellular fluid were performed under aseptic condition.
  • the test samples usually were dissolved in DMSO, stored at -70°C.
  • the cultured cells were added to 96-well culture plate, and each well had a cell number of 1500-7500, after culturing for 24 h, the test drugs with different concentrations were added, and stood continuously for 48 h.
  • GI 50 values about inhibiting growth of cancer cells were determined by SRB (sulfonyl rhodamine B) method.
  • Anticancer drug paclitaxel was used as positive control.
  • A549 lung cancer cells; DU145: prostate cancer cells; KB: nasopharyngeal cancer cells; KB-VIN: drug-resistant nasopharyngeal cancer cells.
  • GI 50 value was the concentration that causes 50% cancer cells growth inhibition, showing anticancer activity. Partial test results of anticancer activity of the compounds of the present invention were shown in Table 1.
  • Table 1 Compounds of Formula I of the present invention and data of their anticancer activity
  • Compound GI 50 ( ⁇ g/ml) A549 DU145 KB KB-VIN 1 0.0006 0.0005 0.0006 0.0006 2 0.0056 0.0046 0.0034 0.0055 3 0.0077 0.0069 0.0085 0.0096 4 0.0088 0.0075 0.0080 0.0092 6 0.061 0.051 0.054 0.059 7 0.075 0.060 0.070 0.063 8* 0.0679 0.0590 0.0660 0.0695 9 5.336 4.764 6.256 4.715 10 0.065 0.056 0.077 0.067 11 0.006 0.006 0.006 0.006 12 0.065 0.060 0.066 0.072 13 0.065 0.055 0.050 0.0639 14* 4,705 7.772 4.568 5.769 18 0.0091 0.0106 0.0661 0.0765 19 0.0010 0.0007 0.0006 0.0008 20 0.0138 0.0115 0.0278

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Claims (9)

  1. Composé de Formule I ou sel pharmaceutiquement acceptable de celui-ci :
    Figure imgb0043
     dans laquelle,
    X et Y chacun indépendamment sont -C(O)-, -NR'-, -CHOR'- ou -CR'R"-; où R' et R" chacun indépendamment sont H, alkyle en C1-6, alcényle en C2-6, alcynyle en C2-6, cycloalkyle en C3-6, alcoxyle en C1-6, alkylamino en C1-6, hydroxyl alkyle en C1-6, alkyle halogéné en C1-6, hydroxyle, acyle, aryle ou hétéroaryle ; et lorsque R' et R" forment un centre chiral à un site de substitution, le composé de Formule I peut être une configuration R ou S unique ou un racémate ;
    R1 représente 1, 2, 3 ou 4 substituants existant sur le cycle benzène, qui sont indépendamment un alcoxyle en C1-6, halogène ou hydroxyle ;
    R2 est un alkyle en C1-6, alcoxyle en C1-6, halogène, hydroxyle, cyano, amino, alkylamino ou dialkylamino ;
    Q et W chacun indépendamment sont N ou CR ; où R est H, halogène, cyano, amino, hydroxyle, alkyle en C1-6, alcoxyle en C1-6, hydroxyl alkyle en C1-6, alkyle halogéné en C1-6, cyano alkyle en C1-6, alkylamino en C1-6, dialkylamino en C1-6, alcényle ou alcényle conjugué en C2-6, alcynyle ou alcynyle conjugué en C2-6, acyle, acylamino, alkylthio, cycloalkyle, hétérocycloalkyle, aryle ou hétéroaryle ;
    R5 et R6 conjointement avec les atomes de carbone liés à eux forment un cycle benzène ou un cycle pyridine éventuellement substitué par 1 ou 2 R3 ;
    R3 indépendamment est H, alkyle en C1-6, alcoxyle en C1-6, fluor, chlore, brome, iode, acyle, alcényle en C2-6, alcynyle en C2-6, hydroxyle, cyano, amino, alkylamino en C1-6, dialkylamino en C1-6, acylamino, alkylthio en C1-6, cycloalkyle en C3-6, hétérocycloalkyle, aryle en C5-10 ou hétéroaryle ;
    n1 = 1 ; et
    n2 = 0.
  2. Composé selon la revendication 1 ou sel pharmaceutiquement acceptable de celui-ci, dans lequel l'halogène est le fluor, le chlore, le brome ou l'iode.
  3. Composé selon la revendication 1 ou 2, dans lequel,
    X et Y chacun indépendamment sont -CHOR'-, -C(O)-, -NR'- ou -CR'R"-; où R' et R" indépendamment sont H, alkyle en C1-4, cycloalkyle en C3-6, alcoxyle en C1-4, alkylamino en C1-4, hydroxyle, acyle, aryle ou hétéroaryle ;
    R1 représente 1 ou 2 substituants existant sur le cycle benzène, qui sont indépendamment un alcoxyle en C1-6, halogène ou hydroxyle ;
    R2 est un alkyle en C1-6, alcoxyle en C1-6, halogène, hydroxyle, cyano, amino, alkylamino ou dialkylamino.
    Q et W chacun indépendamment sont N ou CR ; où R est H, halogène, cyano, amino, hydroxyle, alkyle en C1-4, alcoxyle en C1-4, hydroxyl alkyle en C1-4, cyano alkyle en C1-4, alkylamino en C1-4, dialkylamino en C1-4, alkylthio, cycloalkyle, hétérocycloalkyle, aryle ou hétéroaryle ;
    R5 et R6 conjointement avec les atomes de carbone liés à eux forment un cycle benzène ou un cycle pyridine éventuellement substitué par 1 ou 2 R3 ;
    R3 indépendamment est H, alkyle en C1-4, alcoxyle en C1-4, fluor, chlore, brome, iode, acyle, alcényle en C2-4, alcynyle en C2-4, hydroxyle, cyano, amino, alkylamino en C1-4, dialkylamino en C1-4, acylamino, alkylthio en C1-4, cycloalkyle en C3-6, hétérocycloalkyle, aryle en C5-10 ou hétéroaryle ;
    n1 = 1 ; et
    n2 = 0.
  4. Composé selon la revendication 1 ou 2, dans lequel :
    X et Y chacun indépendamment sont -CHOR'-, -C(O)-, -CR'R"- ou -NR'-; où R' et R" indépendamment sont H, alkyle en C1-4, alcoxyle en C1-4 ou hydroxyle ;
    R1 représente 1 ou 2 substituants existant sur le cycle benzène, qui sont indépendamment un alcoxyle en C1-6, halogène ou hydroxyle ;
    R2 est un alkyle en C1-6, alcoxyle en C1-6, halogène, hydroxyle, cyano, amino, alkylamino ou dialkylamino.
    Q et W chacun indépendamment sont N ou CR ; R est H, halogène, cyano, amino, hydroxyle, alkyle en C1-4, alcoxyle en C1-4, hydroxyl alkyle en C1-4, cyano alkyle en C1-4, alkylamino en C1-4, dialkylamino en C1-4;
    R5 et R6 conjointement avec les atomes de carbone liés à eux forment un cycle benzène ou un cycle pyridine ; le cycle benzène ou pyridine étant éventuellement substitué par 1 ou 2 R3 ;
    R3 indépendamment est H, alkyle en C1-4, alcoxyle en C1-4, fluor, chlore, brome, iode, acyle, alcényle en C2-4, alcynyle en C2-4, hydroxyle, cyano, amino, alkylamino en C1-4, dialkylamino en C1-4, acylamino, alkylthio en C1-4, cycloalkyle en C3-6, hétérocycloalkyle, aryle en C5-10 ou hétéroaryle ;
    n1 = 1 ; et
    n2 = 0.
  5. Composé, qui est choisi parmi :
    N1-[4-(2-chloro)quinazolinyl]-6-méthoxy-1,2,3,4-tétrahydroquinoléine (Composé 1),
    N1-[4-(2-méthyl)quinazolinyl]-6-méthoxy-1,2,3,4-tétrahydroquinoléine (Composé 2),
    N1-[4-(2-méthoxy)quinazolinyl]-6-méthoxy-1,2,3,4-tétrahydroquinoléine (Composé 3),
    N1-[4-(2-méthylamino)quinazolinyl]-6-méthoxy-1,2,3,4-tétrahydroquinoléine (Composé 4),
    N1-[4-(2-méthyl)quinazolinyl]-6-méthyl-1,2,3,4-tétrahydroquinoléine (Composé 6),
    N1-[4-(2-méthyl)quinazolinyl]-6-bromo-1,2,3,4-tétrahydroquinoléine (Composé 7),
    N1-[4-(2-chloro)quinazolinyl]-7-méthoxy-2,3,4,5-tétrahydro-1H-benzo[b]azépine (Composé 10),
    N1-[4-(2-méthyl)quinazolinyl]-4-hydroxyl-6-méthoxy-1,2,3,4-tétrahydroquinoléine (Composé 11),
    N1-[4-(2-chloro)quinazolinyl]-4-éthoxy-6-méthoxy-1,2,3,4-tétrahydroquinoléine (Composé 12),
    N4-[4-(2-chloro)quinazolinyl]-7-méthoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine (Composé 13),
    N1-[4-(2-chloro)quinazolinyl]-6-méthoxy-2,3-dihydroquinoléin-4(1H)-one (Composé 18),
    N4-[4-(2-méthyl)quinazolinyl]-7-méthoxy-3,4-dihydroquinoxalin-2(1H)-one (Composé 19),
    6-méthoxy-2'-méthyl-3,4-dihydro-2H-1,4'-biquinoléine (Composé 20),
    N1-[(3-bromo-5-méthoxycarbonyl)phényl]-6-méthoxy-1,2,3,4-tétrahydroquinoléine (Composé 26),
    N1-[(3-bromo-5-méthylaminoacyl)phényl]-6-méthoxy-1,2,3,4-tétrahydroquinoléine (Composé 28),
    N1-[3-bromo-5-(N-cyclopropylaminoacyl)phényl]-6-méthoxy-1,2,3,4-tétrahydroquinoléine (Composé 29),
    N1-[4-(2-amino-6-chloro)pyrimidinyl]-6-méthoxy-1,2,3,4-tétrahydroquinoléine (Composé 30),
    N1-méthyl-N4-[4-(2-méthyl)quinazolinyl]-7-méthoxy-3,4-dihydroquinoxalin-2(1H)-one (Composé 31),
    2-(N-méthylméthylamino)-4-(6-méthoxy-1,2,3,4-tétrahydro-1-quinolyl)quinazoline (Composé 32),
    2-cyclopropylamino-4-(6-méthoxy-1,2,3,4-tétrahydro-1-quinolyl)quinazoline (Composé 33),
    2-cyclopentylamino-4-(6-méthoxy-1,2,3,4-tétrahydro-1-quinolyl)quinazoline (Composé 34), et
    2-(3-hydroxypropylamino)-4-(6-méthoxy-1,2,3,4-tétrahydro-1-quinolyl)quinazoline (Composé 35).
  6. Composition pharmaceutique, comprenant le composé selon l'une quelconque des revendications 1 à 5, ou un sel pharmaceutiquement acceptable de celui-ci, et un ou plusieurs véhicules ou excipients pharmaceutiquement acceptables.
  7. Procédé pour préparer le composé selon la revendication 1 ou 2 ou un sel pharmaceutiquement acceptable de celui-ci, le procédé comprenant :
    en présence d'un alcali ou d'un acide, l'halogénure substitué de Formule III est mis à réagir avec le composé amine substituée de Formule II dans un solvant pour donner un composé de Formule I,
    Figure imgb0044
    dans lesquelles R1, R2, R5, R6, X, Y, Q, W, n1 et n2 sont définis comme ceux de la Formule I susmentionnée, et
    éventuellement, le composé de Formule I obtenu est converti en un sel pharmaceutiquement acceptable de celui-ci.
  8. Composé selon l'une quelconque des revendications 1 à 5 ou sel pharmaceutiquement acceptable de celui-ci, pour utilisation dans le traitement d'une maladie ou d'un trouble ou dans le soulagement de la sévérité de la maladie ou du trouble.
  9. Composé ou sel pharmaceutiquement acceptable de celui-ci pour utilisation dans le traitement d'une maladie ou d'un trouble ou dans le soulagement de la sévérité de la maladie ou du trouble selon la revendication 8, dans lequel la maladie ou le trouble est choisi(e) parmi un cancer du poumon, un cancer du sein, un cancer de la prostate, un cancer gastrique, un cancer nasopharyngé, un cancer colorectal, un cancer ovarien, un myélome multiple, une mélanine, un glioblastome multiforme, un cancer de la lymphe, une leucémie, un cancer du rein, une tumeur du foie, un sarcome et un cancer de la thyroïde.
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